Intrinsic and extrinsic red blood cell defects

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What is hemolytic anemia?

Hemolytic anemia involves disorders originating from either inside the red blood cell (RBC; intrinsic) or outside of the RBC (extrinsic) that cause fragility and premature breakage and clearance of RBC.

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What is the typical presentation for hemolytic anemia?

• History and examination findings

  • Fatigue, pallor

  • Splenomegaly

  • Dark (tea/cola) urine

• Laboratory findings

  • Low hemoglobin (Hb)

  • Elevated reticulocyte count

  • Elevated (indirect) bilirubin

  • Elevated lactate dehydrogenase (LDH)

  • Decreased haptoglobin

  • Hemoglobinuria

Hemolysis can be classified as either intravascular or extravascular. Although clinical presentation and laboratory findings overlap, there are some key differences that can help in the diagnostic workup of hemolytic anemia. Intravascular hemolysis occurs, as its name suggests, within the blood vessels and is complement or shear mediated. Extravascular hemolysis occurs in the reticuloendothelial system (spleen or liver) as a result of macrophage digestion of RBC.

Intravascular hemolysis typically causes more profound elevation of LDH and reduction of haptoglobin, as well as hemoglobinemia and hemoglobinuria. Conditions causing intravascular hemolysis include paroxysmal cold hemoglobinuria, cold autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and mechanical heart valves. Extravascular hemolysis typically leads to more modest changes in LDH and haptoglobin. Conditions causing extravascular hemolysis include hereditary spherocytosis (and other RBC membrane disorders), hemolytic disease of the newborn, and warm autoimmune hemolytic anemia. Overall, extravascular hemolysis is more common in pediatrics.

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What are the different intrinsic RBC disorders?

The intrinsic RBC disorders involve defects in normal RBC structure and function that lead to decreased RBC survival and hemolysis. They can be broadly categorized as they relate to major components of RBC:

• Membrane disorder

• Enzyme disorder

• Hemoglobinopathies

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What is the normal structure of the RBC membrane?

The RBC membrane is made up of a lipid bilayer overlying a protein cytoskeleton. Channels function to maintain appropriate intracellular fluid content. Defects in any of these components can lead to altered RBC shape and anemia because of shortened RBC life span, increased cellular fragility, and removal in the reticuloendothelial system. Common RBC membrane defects include hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis.

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What is the pathogenesis of hereditary spherocytosis (HS)?

Deficiency of RBC membrane proteins of spectrin, ankyrin, and band 3 lead to an abnormal vertical interaction of the membrane lipid bilayer to the underlying skeleton. This causes RBC to have a spherical shape rather than the normal biconcave disc. These cells have shortened life spans because of increased osmotic fragility and because they are trapped and selectively removed in the spleen. HS is the most common RBC membrane disorder. Although it is most commonly inherited in autosomal dominant fashion, HS can also be the result of autosomal recessive inheritance, which is the most common RBC membrane disorder.

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What is the typical presentation and diagnostic workup of a patient with HS?

Typically children will present in the neonatal period with jaundice or in early childhood with hemolytic anemia with extravascular hemolysis. Because HS is most commonly autosomal dominant, there is often a positive family history of HS. Other suggestive family history could include splenectomy or early cholecystectomy.

Diagnostic workup would first identify features of hemolytic anemia. On the complete blood count (CBC), the mean corpuscular volume (MCV) is typically normal and there is a high mean corpuscular Hb concentration (MCHC). Peripheral smear will show abundant spherocytes. A typical clinical presentation, with spherocytes on smear in the setting of strong positive family history, may be adequate to confirm diagnosis. Confirmatory testing could include osmotic fragility and eosin-5’-maleimide (EMA) flow cytometric binding test. Diagnosis can also be confirmed with genetic testing for the most common genes involved: ANK1, EPB42, SLC4A1, SPTA1, and SPTB.

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What are common complications of HS?

• Chronic hemolysis: This is present for all patients, but there is significant variability from mild to severe chronic anemia.

• Aplastic crisis: Given chronic hemolysis, patients are dependent on ongoing reticulocytosis to maintain their RBCs. Suppression of bone marrow production of reticulocytes, most commonly because of viral infection (often with parvovirus), can lead to a sudden drop in Hb and symptomatic anemia. Typical laboratory findings will be a decline in Hb compared with baseline in the setting of low or absent reticulocyte count. Patients may require supportive RBC transfusion for symptomatic anemia. Patients with HS should be counseled to obtain CBC if they develop fever or other signs of viral illness.

• Hemolytic crisis: Similar to aplastic crisis, viral illness can lead to accelerated hemolysis. The bone marrow’s normal reticulocyte production may not be able to keep up with increased hemolysis. Laboratory findings in this case would also include anemia with elevated reticulocyte count compared with baseline. This can also be managed with supportive RBC transfusion for symptomatic anemia.

• Splenomegaly: This is related to chronic hemolysis. Patients with significant splenomegaly should be cautioned about high-risk contact activities.

• Cholelithiasis: Chronic hemolysis can lead to development of gallstones, obstructive jaundice, and cholecystitis requiring cholecystectomy.

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What are the treatment options for HS?

Typically patients are treated with supportive interventions for complications. Patients should also take folic acid supplementation. For patients with frequent complications or moderate to severe anemia, splenectomy can be considered. Although patients will have continued spherocytosis, splenectomy improves RBC survival to nearly normal, thereby decreasing RBC transfusion needs. The primary risk of splenectomy is lifelong increased risk for severe infection because of encapsulated bacteria. Before splenectomy, patients should receive full immunization series for pneumococcus and meningococcus, including B serotype. Typically lifelong penicillin prophylaxis is recommended, and patients should be promptly evaluated for fever. Partial splenectomy is more controversial but has the potential for some preservation of splenic function with regards to infections.

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